P747: CLINICAL CHARACTERISTICS AND OUTCOME OF EZH2-MUTATED MYELOID NEOPLASMS: MAYO CLINIC EXPERIENCE
Authors: Muhamad Oum, Ahmad Nanaa, Amrutha Mittapalli, Rong He, David Viswanatha, Patricia Greipp, Phuong Nguyen, Dragan Jevremovic, Cecilia Arana Yi, James M Foran, Kebede Benga, Naseema Gangat, Abhishek Mangaonkar, Antoine Saliba, Mrinal Patnaik, William Hogan, Mark Litzow, Ayalew Tefferi, Mithun Shah, Hassan Alkhateeb, Aref Al-Kali
Journal: HemaSphere (2023)

Background: Enhancer of Zeste Homolog 2 (EZH2) gene, located on chromosome 7q36.1, catalyzes the repressive mark of trimethylation of H3K27me3. EZH2 is frequently deleted in myeloid neoplasms and is considered to have an adverse impact on outcome. Somatic mutations in EZH2 (EZH2m) have been reported in 5-10% of chronic myeloid neoplasms (MDS, MPN, CMML), 9% in secondary AML and 2% in de novo AML patients. Aims: To describe patients’ (pts) outcomes with EZH2-mutated myeloid neoplasms (MN). Methods: After institutional review board approval, we retrospectively screened, and chart reviewed 7447 pts samples submitted for next-generation sequencing (NGS) testing between 2016-2022 at Mayo Clinic Cancer Center (Minnesota/Arizona/Florida). Our NGS panel (OncoHeme) included 42 genes recurrently mutated in MN. Biallelic (BI) EZH2 alterations are defined as ≥2 distinct EZH2 mutations, or a single EZH2 mutation plus one of the following abnormalities (1) deletion (7q) or monosomy 7 or (2) EZH2 VAF >50%. All statistical analyses were performed using JMP® 16.2.0 Software. Results: A.Patients’ characteristics: We included 114 EZH2m pts across 6 diagnostic groups [AML (N= 28; 24.5%), MDS (N= 28; 24.5%), MDS/MPN overlaps (N=29; 25.4 %), MPN (N= 24; 21%), CCUS (N=4; 3.5%) and mixed-phenotype acute leukemia (N=1; 0.9%) (excluded from survival analysis). The median age was 72 years, 68% were males, 15% had therapy-related MN (tMN) and 11% were secondary (s)AML. Cytogenetics were abnormal in 61 (56%) of whom 23% (N=14) had either deletion (7q) or monosomy 7. Progression to AML was seen in 14/92 non-AML pts (15%). 29 pts (25%) received Allogeneic HCT. B.EZH2mutations and co-mutations: The median EZH2m VAF was 42% (5-100%) and VAF was significantly higher in MDS/MPN overlap compared to AML (45 vs. 39%; p=.013). Overall, 46 (40%) had BIEZH2m. The most common dominant mutation type was frameshift (N=34; 30%), followed by missense (N=31; 27%), nonsense (N=22; 19%), splice site mutation (N=19; 17%) and stop gain (N=7; 6%). MDS/AML pts were more likely to have a mutation in the SET domain (45% vs. 26%; p=.0443) compared to MPN, MDS/MPN diagnostic group. MDS pts had more missense (36% vs. 12.5%; p=.05) and less nonsense (7% vs. 29%; p=.03) mutations compared to the MPN group. Additionally, MDS/AML pts had more missense mutations compared to MPN and MDS/MPN group (38% vs. 16%; p=.009) and AML pts were less likely to have a splice site mutation compared to MDS/MPN group (7% vs. 28%; p=.04). The median number of co-mutations was 3 (0-6), which occurred across 34 different genes with the most common co-mutations being ASXL1 (N=80; 70%), RUNX1 (N=26; 23%), TET2 (N=25; 22%) JAK2 (N=23; 20%), and SETBP1 (N=15; 13%). C.Survival outcome: After a median follow-up time of 30 months, 61 (54%) died with a median OS (mOS) of 13.6 months in the total cohort. To mitigate the effect of HCT on OS, we censored HCT pts at the transplant date and we found that BIEZH2m pts had significantly shorter median OS than mono-allelic pts (7.2 vs 18.3 months, p=0.03) and pts with >2 co-mutations had worse median OS compared to pts with 2 ≤ co-mutation (8 vs 32 months, p=0.003). Pts with abnormal cytogenetics had non-significant shorter mOS (11 vs 15.6 months, P=0.3). Multivariate analysis demonstrated that pts with >2 co-mutations and BIEZH2m were independent poor prognostic factors for OS with HR of 2.2 (p=.006) and HR of 1.7 (p=.04); respectively. Summary/Conclusion: In this study, we describe the spectrum and characteristics of EZH2 mutations in myeloid neoplasms. We also found that the type of mutation and site of mutation had a significant interaction with the disease classification. BIEZH2m status and EZH2m with >2 co-mutations predicted adverse outcome. Table 1: Hematologic and genetic characteristics of 114 EZH2 mutated patientsKeywords: Myeloid malignancies, EZH2